Effect of protein ingestion on splanchnic and leg metabolism in normal man and in patients with diabetes mellitus.

Wahren, John; Felig, Philip; Hagenfeldt, Lars

doi:10.1172/jci108375

Cited by 354 publications

(161 citation statements)

References 45 publications

(60 reference statements)

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“…Previous studies have also demonstrated a consistently negative amino acid balance in traumatized and septic patients on intravenous nutrition (27), and in patients on enteral nutrition (2). It is, however, obvious that it is possible to obtain a net uptake of amino acids across skeletal muscle in normal individuals simply by increasing the infusion rate of amino acids, which leads to increased arterial levels (Table III [28,29]). …”

Section: Resultsmentioning

confidence: 99%

Transport kinetics of amino acids across the resting human leg.

Lundholm¹,

Bennegård²,

Zachrisson³

et al. 1987

J. Clin. Invest.

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Flux rates of amino acids were measured across the leg after an overnight fast in resting human volunteers. A balanced amino acid solution was, after a primed infusion, continuously infused for 2 h at each of three step-wise and increasing rates corresponding to 83, 16.7, 33.2 Arterial steady state levels were obtained for most amino acids within 30 to 45 min after the primed constant infusion. Leg flux of amino acids switched from a net efflux after an overnight fast to a balanced flux between infusion rates corresponding to 0.2-0.4 g N/kg per d. At 0.8 g N/kg per d essentially all amino acids showed uptake. The infusion of amino acids stimulated leg uptake of glucose and lactate production and decreased FFA release. Oxygen uptake and leg blood flow increased significantly with increased infusion of amino acids. There was significant variability in transport rate among individual amino acids. Branched chain amino acids showed rapid transport and methionine slow transport rate. Only small changes in the muscle tissue concentration of certain amino acids were registered after 6 h of amino acid infusion despite uptake for several hours. When amino acids were infused at a rate corresponding to 0.8 g N/kg per d, the leg uptake of amino acids was 6% and the simultaneous whole body oxidation of infused amino acids was -10%. Net uptake of leucine across the leg per hour was 62% of the muscle pool of free leucine when amino acids were infused at a rate corresponding to 0.4 g N/kg per d. Multiple regression analysis showed that the arterial concentration of an amino acid was the most important factor for uptake, more so than insulin concentration and blood flow.It is concluded that leg exchange of amino acids is large enough to rapidly change the pool size of the amino acids in skeletal muscle, if not counter-regulated by changes in rates of protein synthesis and degradation. Estimates of the capacity for protein synthesis and transfer RNA acceptor sites in muscles agree in order of magnitude with the net uptake of amino

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Section: Resultsmentioning

confidence: 99%

Transport kinetics of amino acids across the resting human leg.

Lundholm¹,

Bennegård²,

Zachrisson³

et al. 1987

J. Clin. Invest.

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“…Nevertheless, its physiologic significance and role in diabetes mellitus has recently been questioned by observations that sustained hyperglucagonemia causes only a transient increase in glucose production in vivo (2)(3)(4)(5), and that prolonged exposure of the liver to hyperglucagonemia in vitro results in diminished ability of glucagon to stimulate glycogenolysis (6), to activate adenylate cyclase (7), and to bind to its plasma membrane receptors (8)(9)(10). However, because glucagon secretion varies throughout the day as a result of intermittent stimuli such as meals (11)(12)(13)(14), exercise (15,16), and stress (17,18), the liver in vivo is usually exposed to fluctuating glucagon levels; thus, conclusions based upon the effects of sustained hyperglucagonemia may not necessarily reflect the actions of glucagon under physiologic conditions. The present studies were, therefore, undertaken to examine the effects on glucose homeostasis of intermittent hyperglucagonemia produced endogenously by administration of the glucagon secretagogue arginine in normal and diabetic man.…”

Section: Introductionmentioning

confidence: 99%

Effect of Intermittent Endogenous Hyperglucagonemia on Glucose Homeostasis in Normal and Diabetic Man

Rizza¹,

Verdonk²,

Miles³

et al. 1979

J. Clin. Invest.

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A B S T R A C T Infusion of glucagon causes only a transient increase in glucose production in normial and diabetic man. To assess the effect ofintermittent endogenous hyperglucagonemia that might more closely reflect physiologic conditions, arginine (10 g over 30 min) was infused four times to 8 normal subjects and 13 insulin-dependent diabetic subjects (4 of whom were infused concomitantly with somatostatin to examine effects ofarginine during prevention ofhyperglucagonemia). Each arginine infusion was separated by 60 min. Diabetic subjects were infused throughout the experiments with insulin at rates (0.07-0.48 mU/kg per min) that had normalized base-line plasma glucose and rates of glucose appearance (Ra) and disappearance (Rd). Basal plasma glucagon and arginine-induced hyperglucagonemia were similar in both groups; basal serum insulin in the diabetics (16+1 ,U/ml, P < 0.05) exceeded those ofthe normal subjects (10+ 1 ,U/ml,P < 0.05) but did not increase with arginine. Serum insulin in normal subjects increased 15-20,U/ml with each arginine infusion. In both groups each arginine inifusion increased plasma glucose and Ra. Increments ofRa in the diabetics exceeded those of normal subjects, (P < 0.02); Rd was similar in both groups. In normal subjects, plasma glucose returned to basal levels after each arginine infusion, whereas in the diabetics hyperglycemia persisted reaching 151 + 15 mg/dl after the last arginine infusion. When glucagon responses were prevented by somatostatin, arginine infusions did not alter plasma glucose or Ra.

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“…Catheter sheaths were placed in the right femoral artery and femoral vein between 7 and 8 A.M. Hepatic vein catheters were inserted under fluoroscopic guidance, and appropriate positioning was confirmed by nonionic contrast injection (18). A femoral artery catheter was inserted through the arterial sheath.…”

mentioning

confidence: 99%

“…A slow infusion of normal saline was used to maintain patency of the catheters. The femoral artery sheath was used for infusion of indocyanine green to measure blood flow in the leg and splanchnic regions using indicator dye dilution techniques (18,19 …”

mentioning

confidence: 99%

Differential Regulation of Protein Dynamics in Splanchnic and Skeletal Muscle Beds by Insulin and Amino Acids in Healthy Human Subjects

2003

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To determine the in vivo effect of amino acids (AAs) alone or in combination with insulin on splanchnic and muscle protein dynamics, we infused stable isotope tracers of AAs in 36 healthy subjects and sampled from femoral artery and vein and hepatic vein. The subjects were randomized into six groups and were studied at baseline and during infusions of saline (group 1), insulin (0.5 mU ⅐ kg ؊1 ⅐ min ؊1 ) (group 2), insulin plus replacement of AAs (group 3) insulin plus high-dose AAs (group 4), or somatostatin and baseline replacement doses of insulin, glucagon and GH plus high dose of AAs (group 5) or saline (group 6). Insulin reduced muscle release of AAs mainly by inhibition of protein breakdown. Insulin also enhanced AA-induced muscle protein synthesis (PS) and reduced leucine transamination. The main effect of AAs on muscle was the enhancement of PS. Insulin had no effect on protein dynamics or leucine transamination in splanchnic bed. However, AAs reduced protein breakdown and increased synthesis in splanchnic bed in a dose-dependent manner. AAs also enhanced leucine transamination in both splanchnic and muscle beds. Thus insulin's anabolic effect was mostly on muscle, whereas AAs acted on muscle as well as on splanchnic bed. Insulin achieved anabolic effect in muscle by inhibition of protein breakdown, enhancing AAinduced PS, and reducing leucine transamination. AAs largely determined protein anabolism in splanchnic bed by stimulating PS and decreasing protein breakdown. Diabetes 52:1377-1385, 2003 I nsulin exerts its anticatabolic effect on protein metabolism by its differential effects on protein synthesis (PS) and breakdown (PB) in many tissue beds (1-4). Human studies have demonstrated that muscle is in a catabolic state after an overnight fast and that it provides amino acids (AAs) to the systemic circulation (2). This AA supply is thought to be crucial for the synthesis of essential proteins, especially in liver (1). Insulin decreases the net efflux of AAs from the muscle bed mainly by inhibiting muscle PB (2). However, insulin has no effect on splanchnic PB and also decreases PS (2). It is unclear whether lack of any stimulatory effect on muscle and splanchnic PS is secondary to reduced intracellular AA concentrations. Our studies, and those of others, suggested that a reduction in circulating AAs (hypoaminoacidemia) or related changes in intracellular AA levels when insulin alone is infused may be the reason why insulin failed to stimulate muscle PS in skeletal muscle (5-8). Animal studies have reported that AAs, especially branched chain AAs, increased the sensitivity of muscle PS to insulin (9). In vitro experiments using large increases in insulin and AA concentrations have also stimulated muscle PS (10,11). Both insulin and AAs have been shown to have independent effects at the translational level of PS (12-15). AAs, especially branched chain AAs, have also been shown to have inhibitory effects on liver PB based on liver perfusion studies (16) and in vivo studies in rodents (12). The independent...

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Effect of protein ingestion on splanchnic and leg metabolism in normal man and in patients with diabetes mellitus.

Cited by 354 publications

References 45 publications

Transport kinetics of amino acids across the resting human leg.

Transport kinetics of amino acids across the resting human leg.

Effect of Intermittent Endogenous Hyperglucagonemia on Glucose Homeostasis in Normal and Diabetic Man

Differential Regulation of Protein Dynamics in Splanchnic and Skeletal Muscle Beds by Insulin and Amino Acids in Healthy Human Subjects

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